Regulation of Sufu activity by p66β and Mycbp provides new insight into vertebrate Hedgehog signaling.
Regulation of Sufu activity by p66β and Mycbp provides new insight into vertebrate Hedgehog signaling.
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DOI：
10.1101/gad.249425.114
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发表时间：
2014-11-15
影响因子：
10.5
通讯作者：
Chuang PT
中科院分区：
文献类型：
--
作者：
Lin C;Yao E;Wang K;Nozawa Y;Shimizu H;Johnson JR;Chen JN;Krogan NJ;Chuang PT
Sufu作为一种主要的负调节因子，对Gli功能的调控是哺乳动物Hedgehog信号转导的关键步骤。Lin等人鉴定了几种Sufu相互作用蛋白，包括p66β和Mycbp。Sufu募集p66β阻断Gli介导的Hh靶基因表达同时，Mycbp在没有Hh刺激的情况下与Gli和Sufu形成复合物，但保持无活性。Hh通路激活导致Sufu/p66β从Gli上解离，使Mycbp能够促进Gli蛋白活性和Hh靶基因表达。融合抑制因子（Sufu）是一种主要的负调节因子，它对Gli功能的控制是哺乳动物Hedgehog（Hh）信号传导的关键步骤，但这是如何在细胞核中实现的尚不清楚。我们发现，Hh信号导致Sufu蛋白水平降低和Sufu从细胞核中的Gli蛋白解离，突出了Sufu在细胞核中的关键功能。通过蛋白质组学方法，我们鉴定了几种Sufu相互作用蛋白，包括p66β（NuRD [核小体重塑和组蛋白去乙酰化酶]阻遏物复合物的成员）和Mycbp（Myc结合蛋白）。在基于细胞的测定和斑马鱼中，p66β负向和Mycbp正向调节Hh信号传导。它们在膜受体Patched和Smoothened以及初级纤毛的下游发挥作用。在Hh靶标的启动子上还以动态方式检测到Sufu、p66β、Mycbp和Gli。我们的研究结果支持一个新的模型Hh信号在细胞核中。Sufu募集p66β阻断Gli介导的Hh靶基因表达同时，Mycbp在没有Hh刺激的情况下与Gli和Sufu形成复合物，但保持无活性。Hh通路激活导致Sufu/p66β从Gli上解离，使Mycbp能够促进Gli蛋白活性和Hh靶基因表达。这些研究提供了新的见解如何腐乳控制Hh信号在细胞核中。
Control of Gli function by Sufu, a major negative regulator, is a key step in mammalian Hedgehog (Hh) signaling. Lin et al. identified several Sufu-interacting proteins, including p66β and Mycbp. Sufu recruits p66β to block Gli-mediated Hh target gene expression. Meanwhile, Mycbp forms a complex with Gli and Sufu without Hh stimulation but remains inactive. Hh pathway activation leads to dissociation of Sufu/p66β from Gli, enabling Mycbp to promote Gli protein activity and Hh target gene expression. Control of Gli function by Suppressor of Fused (Sufu), a major negative regulator, is a key step in mammalian Hedgehog (Hh) signaling, but how this is achieved in the nucleus is unknown. We found that Hh signaling results in reduced Sufu protein levels and Sufu dissociation from Gli proteins in the nucleus, highlighting critical functions of Sufu in the nucleus. Through a proteomic approach, we identified several Sufu-interacting proteins, including p66β (a member of the NuRD [nucleosome remodeling and histone deacetylase] repressor complex) and Mycbp (a Myc-binding protein). p66β negatively and Mycbp positively regulate Hh signaling in cell-based assays and zebrafish. They function downstream from the membrane receptors, Patched and Smoothened, and the primary cilium. Sufu, p66β, Mycbp, and Gli are also detected on the promoters of Hh targets in a dynamic manner. Our results support a new model of Hh signaling in the nucleus. Sufu recruits p66β to block Gli-mediated Hh target gene expression. Meanwhile, Mycbp forms a complex with Gli and Sufu without Hh stimulation but remains inactive. Hh pathway activation leads to dissociation of Sufu/p66β from Gli, enabling Mycbp to promote Gli protein activity and Hh target gene expression. These studies provide novel insight into how Sufu controls Hh signaling in the nucleus.
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DOI：
10.1107/s0907444913028473
发表时间：
2013-12
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Cherry AL;Finta C;Karlström M;Jin Q;Schwend T;Astorga-Wells J;Zubarev RA;Del Campo M;Criswell AR;de Sanctis D;Jovine L;Toftgård R
通讯作者：
Toftgård R
影响因子：
2.7
作者：
Cao, Ting;Wang, Chengbing;Wang, Baolin
通讯作者：
Wang, Baolin
影响因子：
7.5
作者：
Drummond, Iain A.
通讯作者：
Drummond, Iain A.
解码 Hedgehog 信号转导中的磷酸化密码
影响因子：
44.1
作者：
通讯作者：
--
影响因子：
2.9
作者：
Barnfield, PC;Zhang, XY;Hui, CC
通讯作者：
Hui, CC